PROJECT SUMMARY: Frontotemporal dementia (FTD) or frontotemporal lobar degeneration (FTLD) is a group of heterogeneous sporadic and familial neurodegenerative disorders. They are the second most common cause of dementia after Alzheimer's disease (AD) in patients <65 and ~50% of FTLD patients develop abundant tau pathologies in neurons and glia (FTLD-Tau). Exciting new data from Project 2 and provocative recent reports provide models to test novel hypothesis concerning mechanisms of tauopathies. The first hypothesis we test is based on our recent observations that introduction of small amounts of exogenous tau fibril seeds into tau overexpressing cells recruits endogenous tau to fibrillize into abundant tau filamentous structures seeded by the exogenously introduced tau fibrils. These results suggest a seeding mechanism of tau tangle pathogenesis whereby fibrillar tau seeds serve as a nidus for recruiting soluble tau into fibrillar aggregates that enlarge as a result. The second hypothesis we test is based on recent data that tau fibrils spread from cell-to-cell in vitro and in tau transgenic (Tg) mouse models consistent with the notion of a prion-like mechanism for the propagation and spreading of tau pathology and disease progression. Successful completion of the studies to test these hypotheses here will address fundamental disease mechanisms of FTLD-Tau, which, in conjunction with research advances from other projects in this PPG will accelerate efforts to find better therapeutic interventions for patients with diverse FTLDs.